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Documento descargado de http://www.elsevier.es el 14/12/2012. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.BRIEF REPORTS
E. Valverde Molina, V. González Muñiz, J. Gómez-Maldonado, and I. Muñoz Castillo
Servicio de Farmacia, Hospital Carlos Haya, Málaga, SpainAbstract
el inhibidor de la bomba de protones más estable a pH ácido, seevaluó la posibilidad de adicionarlo a las UNP con objeto de facilitar
Introduction: Pantoprazole is a weak base (pka ~ 4) with its stability
in aqueous solution dependent on pH. Keeping in mind that the pH
Métodos: Se determinó por cromatografía líquida de alta resolu-
of the parenteral nutrition units (PNU) can range between 6.0 and
ción (HPLC, del inglés high performance liquid chromatography) la
6.5 and since pantoprazole seems to be the most stable proton pump
riqueza de pantoprazol en una UNP a diferentes intervalos de tiem-
inhibitor (PPI) for pH acid, we want to assess the possibility of adding
it to PNU with the aim of simplifying its administration to patients.Resultados: La determinación cromatográfica de las concentracio-Methods: Using high performance liquid chromatography (HPLC) to
nes de pantoprazol reflejó un rápido y progresivo envejecimiento
measure pantoprazole content in PNU at different time intervals.
de la muestra. Pasadas 24 h la cantidad de fármaco detectado en la
Results: The chromatographic determination of pantoprazole
UNP es inferior al 50% del total adicionado.
concentration reflected a rapid and progressive aging of the sample.Conclusiones: A la vista de estos resultados se desaconseja este ve-
After 24 h the quantity of drug detected in the PNU was below 50%
hículo para la administración de pantoprazol, ya que puede poner
en riesgo la seguridad de los pacientes al infradosificar la medica-
Conclusions: In view of these results, we therefore do not suggest
ción que requieren y exponerlos a los posibles efectos desconoci-
this as a suitable vehicle for pantoprazole administration as it could
dos de los diferentes productos de degradación del fármaco.
put patients at risk of being under-dosed and therefore exposing themto potential unknown side effects of the different drug degradation
Palabras clave: Estabilidad fisicoquímica. HPLC. Pantoprazol. Nutrición pa-renteral.Key words: Drug stability. HPLC. Pantoprazole. Parenteral nutrition.Estabilidad de pantoprazol en unidades para nutriciónparenteral.INTRODUCTIONIntroducción: El pantoprazol es una base débil (pka ~ 4) y su esta-
Pantoprazole, one of the most used proton pump inhibitors, is
bilidad en solución acuosa es dependiente del pH. Teniendo en
a weak base (pka ~ 4) with its stability in aqueous solution
cuenta que el pH de las unidades de nutrición parenteral (UNP)
dependent on pH. Its hydrolysis increases as pH decreases. At
puede oscilar entre 6,0 y 6,5, y puesto que pantoprazol parece ser
room temperature, its degradation half-life varies to a few minutesat pH 1.0-2.01 and 220 h to pH 7.8,2 with optimal stability atpH 9.
All benzimidazoles used as PPI are unstable in acid
environments, but previous studies have shown significantdifferences in the degradation time of different molecules based
Correspondence: E. Valverde Molina.Servicio de Farmacia. Hospital Carlos Haya.
on the pH levels in which they are found. Pantoprazole is the PPI
Camino de Antequera, s/n. 29011 Málaga. España.
least sensitive to acid pH.3 Keeping in mind that the pH of
E-mail: [email protected]
parenteral nutrition units (PNU) can range between 6.0 and 6.5,
Accepted for publication: September 16, 2008.
the possibility of adding pH to the units was evaluated.
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Valverde Molina E et al. Stability of Pantoprazole in Parenteral Nutrition Units
Pantoprazole is widely used in hospitals. In hospitals, patients
HPLC water (Merck S.A.), and its stability was determined for
with a significant amount of fluid therapy due to the high quantity
at least 1 week at room temperature (variation coefficient of
of intravenous medication they need is frequently seen. The
3.47%). An aliquot of IS (20 µg/mL) was injected at each time
reduction of perfusion volumes for patients who require restricted
interval with no changes in the appearance of the peak and no
fluid therapy is very helpful for clinics. A regular way of decreasing
fluid volume is by adding drugs to the PNU, and this also decreases
The standard solution prepared was with a pantoprazole
concentration of 160 µg/mL, and the preparation of sodium
After reviewing bibliographic information, studies on PPI
pantoprazole in commercial freeze-dried powder was dissolved
stability in various solutions were found,4-6 but no study made
into an injectable solution of 250 mL of PNU. As has occurred
with other authors,5 pure pantoprazole could not be obtained bythe manufacturer for use as a reference standard. Therefore,“Anagastra®” the commercial product for injections, was used to
prepare the standards. Five calibrators were prepared by dilutingthe standard solution of pantoprazole with the PNU solution at
Preparation of the Parenteral Nutrition Unit
concentrations of 2, 5, 10, 15, and 30 µg/mL. Both thepropylparaben and pantoprazole standard solutions were evaluated
Standard type PNU was used (Table 1) and prepared according
Analysis of Samples by Using High PerformancePreparation of the SampleLiquid Chromatography
To prepare the sample, 40 mg vials of sodium pantoprazole in
The original method by Dentinger et al5 was used for pantoprazole
freeze-dried powder for injectable solutions were used
determinations by HPLC, with small modifications made by
(Anagastra®, Altana Pharma AG). Ten mL of the PNU solution
Johnson.4 Equipment from HPLC Waters Corporation 1525, a
was put into each vial and shaken in a vortex; later, 3 L of PNU
binary pump and a VIS-UV W 2487 detector was used. For data
were added to the bottle by syringe, and a final concentration of
acquisition and processing, Breeze (Waters Corporation) software
13.3 µg/mL was drawn. The sample time interval was set at 3,
was used. Chromatographic conditions used included the reversed
6, 9, 12, 24, and 48 h. PNU were kept at room temperature and
phase Symmetry 300™ C18 column 3.3 µm 4.6×150 mm used at
protected from the light. The PNU pH was determined before
room temperature and with a wavelength of 280 nm. The mobile
the addition of pantoprazole and at 0, 24, and 48 h after its
phase consisted of a 40% (v/v) proportion of HPLC grade
addition. Samples were prepared aseptically, but their sterility
acetonitrile (Merck SA) in a 50 mM (pH 7) phosphate buffer
(Merck S.A. Lot 4871). The phosphate buffer was prepared withHPLC grade water and was filtered by 0.2 µm filter membranes
Preparation of the Calibration Curve and Internal
(Millex® GS. Millipore). The mobile phase was degassed using
Standard
helium, and the flow rate was set at 1 mL/min. The final injectionvolume was 30 µL, and determinations were carried out in
An internal standard solution was prepared (IS), with propylparaben
duplicate. For integrating the chromatograms, the retention times
(Farmaquímica Sur SL), at a final concentration of 0.2 mg/mL
for pantoprazole and the IS were set after reevaluating the methodat 3.5 and 5.7 min, respectively.Analysis of SamplesTable 1. Quantitative Composition of Parenteral Nutrition
For each analysis, 500 µL of PNU with added pantoprazole were
drawn together, and this was placed in a centrifuge tube.
Subsequently, 100 µL of IS solution (0.2 mg/mL) and 400 µL of
acetonitrile were added. This was shaken for 20 s in a vortex and
centrifuged for 10 min at 10 000 rpm and at room temperature.
The supernatant was collected in a centrifuge tube, and 100 µL
were placed in microvials for later analysis by HPLC.
Data Analysis
Pantoprazole stability was determined through evaluation of the
concentration at each time interval.
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Valverde Molina E et al. Stability of Pantoprazole in Parenteral Nutrition Units
Table 2. Pantoprazole Concentration Data in the Parenteral
For finding pantoprazole determinations, the HPLC method
Nutrition Unit at Time Intervals of the Trial
was selected because of its efficacy, sensitivity, and repeatability.The selection of a sampling schedule for taking measurements
Pantoprazole Concentration (SD), µg/mL
was done keeping in mind that approximately 6 h pass for
parenteral nutrition preparation to be completed and administered
to the patient. Also, considering that parenteral nutrition mixtures
perfuse in less than 48 h and usually no more than 24 h, 48 h
was established as the upper time limit and 24 h as the critical
A yellow coloration was observed in the PNU tested, which in
view of data obtained, seems to be related to the appearance of
degradation products from pantoprazole. Nevertheless, the
Johnson4 study concludes that the appearance of a yellow tonalityin pantoprazole solutions is not related to an unacceptable decreasein the concentration of the molecule. In consideration of these
apparently contradictory results, it would be necessary to designnew studies which correlate the variation of pantoprazole solution
Chromatographic determination of pantoprazole concentrations
tonality with its percentage of degradation.
at different sampling times (Table 2) shows the sample’s aging
Pantoprazole is one of the most stable PPI in terms of pH change.
(the decrease of pantoprazole over time). This activity loss is
However, it has a very fast activity loss in PNU; its concentration
related to the decrease of pantoprazole content. Less than 80%
falls below the tolerable lower limits within a few hours after its
of added pantoprazole could be detected in the PNU after 6 h,
addition; and its concentrations reduce to less than 50% at 24 h.
and its concentration was reduced to less than 50% at 24 h.
Based on these results, this vehicle for pantoprazole administration
With the aim of seeing if the added drug could destabilize the
is not recommended, as it does not provide any benefit for patients,
mixture, pH measurements of PNU were carried out simultaneously
but could put them at risk of underdosing their needed medication,
with the chromatographic determination of pantoprazole. No
and could expose them to possible unknown effects from the
significant modifications were detected in the pH evolution of
PNU throughout the study, and an average pH of 6.11 (6.16-6.06)
The results obtained in this study encourage pharmacy
was established. However, PNU color changes were observed,
departments to communicate the risk of adding unstudied drugs
with a yellowish color at 12 h which had intensified after 24 h.
to parenteral solutions and also promote research on the stabilityof other compounds with the end of ensuring correct dosage andminimizing possible dangers of inappropriate drug use.DISCUSSION
This study was designed to determine stability, and therefore
References
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IN THE COURT OF COMMON PLEAS OF LYCOMING COUNTY, PENNSYLVANIA LARRY A. BRION and BARBARA, Plaintiffs : No. 99-00008 : R. SOUNDARARAJAN, M.D., F.A.C.S., and SANDY & ROCKOFF UROLOGICAL ASSOCIATES, : Summary Judgment Defendants OPINION AND ORDER This matter came before the Court on the defendant’s Motion forSummary Judgment and the plaintiffs’ Motion to Amend/M